1. Field of the Invention
The present invention relates to the treatment of allergic or inflammatory diseases or other Syk-mediated diseases or conditions. More particularly, the present invention relates to the topical or systemic administration of certain 3,6-substituted imidazol[1,2-b]pyridazine analogs for the treatment of such diseases or conditions.
2. Description of the Related Art
Syk is a tyrosine kinase that plays a critical role in mast cell degranulation, eosiniphil activation, lipid mediator synthesis and cytokine production. Accordingly, Syk kinase is implicated in various inflammatory and allergic disorders in particular asthma.
It has been shown that Syk binds to the phosphorylated gamma chain of the high affinity IgE receptor (Fcε RI) signaling via N-terminal SH2 domains and is essential for downstream signaling [Taylor et al, Molecular and Cellular Biology 1995; 15:4149-4157]. Syk kinase is important in the intracellular propagation of signaling following the crosslinking of the high affinity IgG receptor (FcγRI) by IgG. Since the mediators released as the results of Fcε RI and FcγRI are responsible at least in part for adverse effects associated with allergic responses or inflammation, compounds that inhibit Syk kinase may be effective in inhibiting those adverse effects [Sirganian et. al. Molecular Immunology 2002, 38:1229-1233].
The term “Syk-mediated disease” or “Syk-mediated condition”, as used herein, means any disease or other deleterious condition in which Syk protein kinase is known to play a role. Such conditions include, without limitation, inflammation and allergic disorders, especially asthma.
As taught in WO 2004/014382 (Rigel Pharmaceuticals) certain 2,4-pyridinediamine compounds have Syk kinase inhibitory activity. Lai et. al. describe a series of oxindoles having Syk kinase activity [Biorganic and Medicinal Chemistry Letters 2003, 13:3111-3114. Cywin et. al. describe the activity of a series of [1,6]naphthyridine compounds that inhibit Syk kinase [Biorganic and Medicinal Chemistry Letters 2003, 13:1415-1418]. Yamamoto et. al. describe an orally available imidazo[1,2,c]pyrimidine Syk kinase inhibitor [Journal of Pharmacology and Experimental Theapeutics 2003, 306:1174-1181]. WO2004/085409 discloses 5-substituted 2,3-diaminopyrazines.